Stereo-random synthesis of highly functionalized proline analogues by azomethine cycloaddition

Highly substituted proline analogues were synthesized on Wang-resin bearing bisprotected histidine as starting material. The proline analogues (1,5-diazabicyclo[3.3.0]octane-2-carboxylic acid) were generated by 1,3-dipolar cycloaddition of azomethine ylides with maleimides, thus creating a library of maximum stereochemical diversity. Every compound set with the same empirical formula can theoretically consist of four diastereomers and can be tested in biological assays as mixture. Additionally different methods for the acylation of the proline nitrogen were evaluated.